1-(2&#39;-Aroyl eth-1&#39;yl) 2-(4&#34;-acetamido piperazine-1&#34;yl methyl) benzimidazoles and their therapeutical applications

ABSTRACT

Compounds of the formula ##STR1## where Ar is phenyl, substituted phenyl, α-furyl or α-thienyl, and 
     R is NH 2 , NHR 1  wherein R 1  is alkyl or cycloalkyl, or NR 1  R 2  wherein 
     R 1  and R 2  are alkyl or --N 1  R 1  R 2  is piperidino, pyrrolidino, morpholino or hexamethyleneimino. The compounds are prepared by reacting the corresponding Ar-substituted chloromethylated benzimadazole with the corresponding R-substituted piperazine. The compounds possess gastric antisecretory, anti-ulcerous, spasmolytic, anti-cholinergic, anti-bronchoconstrictive, analgesic, anti-inflammatory, anti-hypertensive and diuretic properties.

This is a division of application Ser. No. 643,490, filed Dec. 22, 1975, now U.S. Pat. No. 4,072,682.

The present invention concerns 1-(2'-aroyl eth-1' yl) 2-(4"-acetamido piperazine-1" yl methyl) benzimidazoles, their method of preparation and their application in therapeutics.

The compounds of the invention correspond to the following general formula (I): ##STR2## in which: Ar designates:

A phenyl nucleus which may be substituted by methoxy alkyl having 1 to 4 carbon atoms, nitro, or halogen, or

α-furyl or α-thienyl, and

R designates:

--NH₂,

Nhr' where R' is alkyl having from 1 to 4 carbon atoms, or cycloalkyl having at least 6 carbon atoms, or

Nr₁ r₂ where R₁ and R₂ designate an alkyl group having 1 to 4 carbon atoms or form together with the nitrogen atom to which they are linked, a heterocyclic radical chosen from piperidino, pyrrolidino, morpholino and hexamethyleneimino.

The method of the invention consists of condensing a compound of formula (II): ##STR3## where Ar has the same significance as in formula (I), with a piperazine of formula (III): ##STR4## in which R has the same significance as in formula (I).

This condensation is effected in an ethyl acetate medium and in the presence of sodium carbonate.

The compounds of formula (II) are obtained by reacting an alcohol of formula (IV): ##STR5## where Ar has the same significance as in formula (I), with thionyl chloride of formula (V):

    so cl.sub.2                                                (V)

the preparation of the derivatives of formula (IV) being described in French application No. 72.19540 published under the No. 2 186 251.

The following preparations are given as examples to illustrate the invention.

EXAMPLE 1 1-(2'-benzoyl eth-1' yl) 2-(4"-N-isopropylacetamido piperazine-1" yl) benzimidazole dimaleate -- Code number: 73 0442 First step: 1-(2'-benzoyl eth-1' yl) 2-(chloromethyl) benzimidazole -- code number: 72 370

To a suspension of 0.62 mole of 1-(2'-benzoyl ethyl) 2-methanol benzimidazole in 480 ml of chloroform was added, at 15° C and within 1 hour, a solution of 0.95 mole of thionyl chloride in 270 ml of chloroform. After contacting for 2 hours at room temperature, the excess thionyl chloride was evaporated and the methanol solution of the chlorhydrate was neutralized with sodium bicarbonate. After filtration and evaporation, the crude base was recrystallized in ethyl acetate.

Melting point : 109° C

Yield: 67 %

Empirical formula: C₁₇ H₁₅ Cl N₂ O

Elementary analysis:

    ______________________________________                                                       C       H         N                                              ______________________________________                                         Calculated (%)  68.34     5.06      9.38                                       Obtained (%)    68.14     5.18      9.24                                       ______________________________________                                    

Second step: 1-(2'-benzoyl eth-1' yl) 2-(4"-N-isopropyl-acetamido piperazine-1" yl) benzimidazole dimaleate Code number: 73 0442

To a suspension of 0.1 mole of 1-(2' benzoyl-eth-1' yl) 2-(chloromethyl) benzimidazole obtained in the previous step, in 250 ml of ethyl acetate, was added 0.15 mole of sodium carbonate then 0.12 mole of 1-(N-isopropylacetamido) piperazine. After a reflux of 6 hours, the reaction medium was taken up with 600 ml of water. The organic phase was decanted, then dried. After evaporation of the ethyl acetate, the crude mass was salified in 200 ml of acetone by means of maleic acid.

Melting point: 151° C

Yield: 82 %

Empirical formula: C₃₄ H₄₁ N₅ O₁₀

Elementary analysis:

    ______________________________________                                                       C       H         N                                              ______________________________________                                         Calculated (%)  60.08     6.08      10.30                                      Obtained (%)    59.90     6.08      10.45                                      ______________________________________                                    

EXAMPLE 2 1-(2'-benzoyl eth-1' yl) 2-(4"-pyrrolidinocarbonylmethyl piperazine-1" yl methyl) benzimidazole Code number : 73 0458

To a suspension of 0.1 mole of 1-(2'-benzoyl eth-4' yl) 2-(chloromethyl) benzimidazole obtained in the first step of example 1, in 250 ml of ethyl acetate was added 0.15 mole of sodium carbonate, then 0.12 mole of 1-pyrrolidinocarbonylmethyl piperazine. After a reflux of 1 hour, the sodium carbonate was separated by filtration and the ethyl acetate phase was concentrated.

The crude base obtained was purified by recrystallization in ethanol.

Melting point: 196° C

Yield: 80 %

Empirical formula: C₂₇ H₃₃ N₅ O₂

Elementary analysis:

    ______________________________________                                                       C       H         N                                              ______________________________________                                         Calculated (%)  70.56     7.24      15.24                                      Obtained (%)    70.58     7.38      15.40                                      ______________________________________                                    

The compounds shown in table I following were prepared according to the operating mode of the second step of example 1.

                                      TABLE I                                      __________________________________________________________________________      ##STR6##                                                                                                           Melt-                                     Code                             Mole-                                                                              ing                                       num-                    Empirical                                                                               cular                                                                              point                                                                              Yield                                                                              Elementary analysis               ber Ar        R         formula  weight                                                                             (° C)                                                                       (%)         C  H  N                   __________________________________________________________________________     74 0145                                                                             ##STR7## NH CH.sub.3                                                                              C.sub.32 H.sub.37 N.sub.5 O.sub.10                                                      651.66                                                                             152 69  Calculated (%) Obtained                                                                58.98 58.68                                                                       5.72 5.85                                                                         10.75 10.59         74 0144                                                                             ##STR8## NH C.sub.2 H.sub.5                                                                       C.sub.33 H.sub.39 N.sub.5 O.sub.10                                                      665.69                                                                             142 90  Calculated (%) Obtained                                                                59.54 59.50                                                                       5.91 5.92                                                                         10.52 10.65         74 0159                                                                             ##STR9## NH C.sub.3 H.sub.7 (n)                                                                   C.sub.34 H.sub.41 N.sub.5 O.sub.10                                                      679.71                                                                             128 50  Calculated (%) Obtained                                                                 60.08 60.07                                                                      6.08 6.24                                                                         10.30 10.10         74 0186                                                                             ##STR10##                                                                               NH C.sub.4 H.sub.9 (n)                                                                   C.sub.35 H.sub.43 N.sub.5 O.sub.10                                                      693.73                                                                             132 67  Calculated (%) Obtained                                                                60.59 60.63                                                                       6.25 6.41                                                                         10.10 10.04         74 0187                                                                             ##STR11##                                                                               NH C.sub.4 H.sub.9 (i)                                                                   C.sub.35 H.sub.43 N.sub.5 O.sub.10                                                      693.73                                                                             137 71  Calculated (%) Obtained                                                                60.59 60.79                                                                       6.25 6.24                                                                         10.10 10.05         74 0180                                                                             ##STR12##                                                                               N (CH.sub.3).sub.2                                                                       C.sub.33 H.sub.39 N.sub.5 O.sub.10                                                      665.69                                                                             170 86  Calculated (%) Obtained                                                                59.54 59.36                                                                       5.91 5.78                                                                         10.52 10.30         74 0453                                                                             ##STR13##                                                                               N (C.sub.3 H.sub.7(i)).sub.2                                                             C.sub.37 H.sub.47 N.sub.5 O.sub.10                                                      721.78                                                                             110 40  Calculated (%) Obtained                                                                61.57 61.80                                                                       6.56                                                                              9.70 9.74           74 0184                                                                             ##STR14##                                                                               N (C.sub.2 H.sub.5).sub.2                                                                C.sub.35 H.sub.43 N.sub.5 O.sub.10                                                      693.75                                                                             154 78  Calculated (%) Obtained                                                                60.59 60.50                                                                       6.25 6.37                                                                         10.10  9.92         74 0196                                                                             ##STR15##                                                                               N (C.sub.3 H.sub.7(n)).sub.2                                                             C.sub.37 H.sub.47 N.sub.5 O.sub.10                                                      721.79                                                                             143 78  Calculated (%) Obtained                                                                61.57 61.63                                                                       6.56 6.80                                                                         9.70 9.65           74 0160                                                                             ##STR16##                                                                                ##STR17##                                                                               C.sub.35 H.sub.41 N.sub.5 O.sub.11                                                      707.72                                                                             187 88  Calculated (%) Obtained                                                                59.40 59.70                                                                       5.84 5.64                                                                         9.90 9.70           74 0195                                                                             ##STR18##                                                                                ##STR19##                                                                               C.sub.37 H.sub.45 N.sub.5 O.sub.10                                                      719.77                                                                             149 77  Calculated (%) Obtained                                                                61.74 61.61                                                                       6.30 6.56                                                                         9.73 9.91           74 0655                                                                             ##STR20##                                                                               NH C.sub.4 H.sub.9 (t)                                                                   C.sub.35 H.sub. 43 N.sub.5 O.sub.10                                                     693.73                                                                             166 50  Calculated (%) Obtained                                                                60.59 60.57                                                                       6.25 6.47                                                                         10.10 10.04         74 0656                                                                             ##STR21##                                                                                ##STR22##                                                                               C.sub.37 H.sub.45 N.sub.5 O.sub.10                                                      719.770                                                                            150 55  Calculated (%) Obtained                                                                61.74 61.47                                                                       6.30 6.57                                                                         9.73 9.60           74 0698                                                                             ##STR23##                                                                               NH C.sub.3 H.sub.7 (i)                                                                   C.sub.32 H.sub.39 N.sub.5 O.sub.11                                                      669.672                                                                            161 50  Calculated (%) Obtained                                                                57.39 57.24                                                                       5.87 5.73                                                                         10.46 10.26         74 0699                                                                             ##STR24##                                                                               NH C.sub.3 H.sub.7 (i)                                                                   C.sub.32 H.sub.39 N.sub.5 O.sub.10 S                                                    685.738                                                                            170 62  Calculated (%) Obtained                                                                56.04 55.89                                                                       5.73 5.43                                                                         10.21 10.22         74 0700                                                                             ##STR25##                                                                               NH C.sub.3 H.sub.7 (i)                                                                   C.sub.35 H.sub.43 N.sub.5 O.sub.11                                                      709.734                                                                            150 62   Calculated (%) Obtained                                                               59.23 59.31                                                                       6.11 6.07                                                                         9.87 9.79           75 0009                                                                             ##STR26##                                                                               NH C.sub.3 H.sub.7 (i)                                                                   C.sub.35 H.sub.43 N.sub.5 O.sub.10                                                      693.734                                                                            146 61  Calculated (%)  Obtained                                                               60.59 60.44                                                                       6.25 6.24                                                                         10.10 10.11         75 0012                                                                             ##STR27##                                                                               NH C.sub.3 H.sub.7 (i)                                                                   C.sub.34 H.sub.40 ClN.sub.5 O.sub.10, H.sub.2                                           732.157                                                                            151 45  Calculated (%) Obtained                                                                55.77 55.66                                                                       5.78 5.74                                                                         9.57 9.57           75 0010                                                                             ##STR28##                                                                               NH C.sub.3 H.sub.7 (i)                                                                   C.sub.35 H.sub.43 N.sub.5 O.sub.11                                                      709.734                                                                            122 60  Calculated (%) Obtained                                                                59.23 58.93                                                                       6.11 6.31                                                                         9.87 9.78           75 0011                                                                             ##STR29##                                                                               NH C.sub.3 H.sub.7 (i)                                                                   C.sub.35 H.sub.43 N.sub.5 O.sub.11                                                      709.734                                                                            154 60  Calculated (%) Obtained                                                                59.23 59.00                                                                       6.11 6.14                                                                         9.87 9.87           75 0102                                                                             ##STR30##                                                                               NH.sub.2  C.sub.31 H.sub.35 N.sub.5 O.sub.10 , 1,75 H.sub.2                              O        669.158                                                                            140 50  Calculated (%) Obtained                                                                55.64 55.48                                                                       5.80 5.56                                                                         10.47 10.37         74 0751                                                                             ##STR31##                                                                                ##STR32##                                                                               C.sub.36 H.sub.43 N.sub.5 O.sub.10                                                      705.744                                                                            150 85  Calculated (%) Obtained                                                                61.26 61.01                                                                       6.14 6.10                                                                         9.92 9.70           74 0747                                                                             ##STR33##                                                                               NH C.sub.3 H.sub.7 (i)                                                                   C.sub.34 H.sub.40 N.sub.6 O.sub.12                                                      724.708                                                                            134 59  Calculated (%) Obtained                                                                56.34 56.18                                                                       5.56 5.64                                                                         11.60 11.43         __________________________________________________________________________

The compounds of formula (I) were tested on laboratory animals and showed gastric antisecretory, anti-ulcerous, spasmolytic in vivo, anti-cholinergic and antibronchoconstrictive, analgesic, anti-inflammatory, anti-hypertensive and diuretic properties.

(1) Gastric antisecretory properties

Administered intraduodenally to a rat, the compounds of formula (I) are capable of reducing gastric secretion measured after Shay ligature.

As examples, table II following gives the results obtained.

                  Table II                                                         ______________________________________                                                                  Reduction of volume                                   Code No of Dose administered                                                                            of gastric secretion                                  tested compound                                                                           (mg/kg/i.d.)  (%)                                                   ______________________________________                                         75,009     10            62                                                    73 0458    2             19                                                    75 0010    25            82                                                    73 0442    2.1           68                                                    75 001-    25            75                                                    74 0145    1.6           88                                                    75 0012    10            63                                                    74 0144    1.6           85                                                    75 0102    10            91                                                    74 0159    1.5           77                                                    74 0186    1.5           67                                                    74 0187    1.5           78                                                    74 0180    1.5           86                                                    74 0184    1.5           77                                                    74 0196    1.5           74                                                    74 0160    1.5           45                                                    74 0751    4.5           69                                                    ______________________________________                                    

(2) Anti-ulcerous properties

Compounds of formula (I), administered orally, reduce the area of ulcerations caused in a rat under stress for 7 hours.

Thus, table III gives the results obtained by administration of the different compounds of formula (I).

                  TABLE III                                                        ______________________________________                                                                  Percentage reduction                                  Code No of Dose administered                                                                            of stress ulcers                                      tested compound                                                                           (mg/kg/p.o.)  (%)                                                   ______________________________________                                         73 0458    5             77                                                    73 0442    5.2           99                                                    74 0145    7.7           100                                                   74 0144    7.7           99                                                    74 0159    7.5           100                                                   74 0186    7.4           98                                                    74 0187    7.4           100                                                   74 0180    7.7           100                                                   74 0184    7.4           100                                                   74 0196    7.3           88                                                    74 0160    6             76                                                    74 0195    7.1           59                                                    75 0009    20            90                                                    75 0010    20            77                                                    75 0011    20            51                                                    75 0012    20            64                                                    75 0102    10            100                                                   ______________________________________                                    

Furthermore, the compounds of formula (I) administered intraduodenally reduce the ulceration area caused by ligature of the pylorus of a rat (Shay's ulcers).

The results obtained are shown in table IV.

                  TABLE IV                                                         ______________________________________                                                                  Percentage reduction                                  Code No of Dose administered                                                                            of Shay's ulcer                                       tested compound                                                                           (mg/kg/i.d.)  (%)                                                   ______________________________________                                         73 0458    10            90                                                    75 0009    20            56                                                    73 0442    7.6           88                                                    75 0010    40            86                                                    74 0145    15.5          100                                                   75 0011    40            78                                                    74 0144    15.5          98                                                    75 0012    10            73                                                    74 0159    15.1          100                                                   75 0102    10            74                                                    74 0186    14.8          75                                                    74 0187    14.8          94                                                    74 0180    7.7           94                                                    74 0453    7.3           82                                                    74 0184    7.4           100                                                   74 0196    7.3           90                                                    74 0160    15            99                                                    74 0195    14.2          86                                                    74 0751    10            89                                                    ______________________________________                                    

(3) Spasmolytic in vivo properties

The compounds of formula (I), administered intraduodenally are capable of reducing the contractions of the jejunal ansa of a rabbit, caused by electric stimulation.

The results obtained are shown in table V following:

                  TABLE V                                                          ______________________________________                                                                 Diminution of contractions                             Code No of Dose administered                                                                           of the jejunum for more                                tested compound                                                                           (mg/kg/i.d.) than an hour - (%)                                     ______________________________________                                         75 0102    25           80                                                     73 0442    26.5         67                                                     74 0144    15.5         43                                                     74 0180    15.4         50                                                     74 0184    14.9         39                                                     ______________________________________                                    

The same test was studied with the uterine horn of a female rabbit.

For example, compound No 73.0442, administered at a dose of 53 mg/kg/i.d. reduces by 85 % for more than an hour, the contractions of the uterine horn of a female rabbit caused by electric stimulation.

(4) Anticholinergic and antibronchoconstrictive properties

Injected intravenously or intraduodenally, the compounds of formula (I) are capable of opposing bronchoconstriction caused in a guinea-pig by intravenous injection of acetylcholine and evaluated by Konzett's method. Table VI following shows the results obtained.

                  TABLE VI                                                         ______________________________________                                         Code No of                                                                             Mode of  Dose        Percentage inhibition of                          compound                                                                               adminis- administered                                                                               the bronchoconstriction                           tested  tration  (mg/kg)     (%)                                               ______________________________________                                         73 0458 i.d.     100         67                                                73 0442 i.d.     25          100                                               74 0145 i.v.     0.5         75                                                74 0144 i.v.     4           100                                               74 0159 i.v.     5           100                                               74 0186 i.v.     2           100                                               74 0187 i.v.     5           100                                               74 0180 i.v.     5           100                                               74 0453 i.v.     2.5         100                                               74 0184 i.v.     4           100                                               74 0195 i.d.     25          60                                                ______________________________________                                    

(5) Analgesic properties

The compounds of formula (I), administered orally to a mouse, are capable of reducing the number of painful stretchings following intraperitioneal injection of acetic acid.

The result obtained are shown in table VII.

                  TABLE VII                                                        ______________________________________                                                                  Percentage diminution                                 Code No of Dose administered                                                                            painful stretchings                                   compound tested                                                                           (mg/kg/p.o.)  (%)                                                   ______________________________________                                         73 0442    100           80                                                    74 0145    10            70                                                    74 0144    40            92                                                    74 0159    50            40                                                    74 0186    40            77                                                    74 0187    50            42                                                    74 0180    50            53                                                    74 0184    50            63                                                    74 0195    50            53                                                    ______________________________________                                    

(6) Anti-inflammatory properties

These properties are revealed, by a diminution following oral administration of the compounds of formule (I), of the local oedema caused in a rat by sub-plantar injection of a phlogogenic agent, such as carragenine.

Table VIII gives as examples the results obtained with different compounds of formula (I).

                  TABLE VIII                                                       ______________________________________                                                                  Percentage reduction                                                           of sub-plantar                                        Code No of Dose administered                                                                            oedema                                                compound tested                                                                           (mg/kg/p.o.)  (%)                                                   ______________________________________                                         74 0145    10            40                                                    74 0144    30            35                                                    74 1059    50            57                                                    74 0186    40            48                                                    74 0187    50            47                                                    74 0180    50            47                                                    74 0184    50            65                                                    74 0160    50            50                                                    ______________________________________                                    

(7) Anti-hypertensives properties

The compounds of formula (I) are capable, 4 hours after their oral injection, of bringing the arterial pressure down to normal in genetically hyperstressed vigil rats (S.H.R.).

Thus, administration of compounds No 750 011 and 740 747 respectively at doses of 10 mg/kg/p.o. and 150 mg/kg/p.o. are capable of bringing the arterial pressure down to normal in 4 animals out of 7.

(8) Diuretic properties

The compounds of formula (I), administered orally to a rat, increase the volume of urine emitted, relative to controls, the volume being measured for the 6 hours following administration.

For example, compound 750 011 has a DE 50 equal to 1 mg/kg/p.o.

In addition, since the compounds of formula (I) are not very toxic, as can be seen from table IX following, the difference between pharmacologically active doses and lethal doses is sufficient, for these compounds, to permit their use in therapeutics.

                  TABLE IX                                                         ______________________________________                                         Code No of       Lethal dose 50 (mouse)                                        compound tested  (mg/kg/p.o.)                                                  ______________________________________                                         73 0458          >2 000                                                        75 0009          1 800                                                         73 0442          798                                                           75 0010          1 200                                                         74 0145          180                                                           75 0011          120                                                           74 0144          310                                                           75 0012          1 300                                                         74 0159          1 250                                                         75 0102          1 300                                                         74 0186          360                                                           74 0187          1 600                                                         74 0180          716                                                           74 0453          1 000                                                         74 0184          1 300                                                         74 0196          2 100                                                         74 0160          1 700                                                         74 0195          >2 000                                                        74 0751          1 100                                                         74 0747          2 200                                                         ______________________________________                                    

The compounds of formula (I) are principally indicated on the treatment of gastroduodenal ulcers, hyperchlorhydrias, visceral spasms, asthma, hypertension oedemas, pains of different, particularly inflammatory, origin.

They will be administered orally in the form of tablets, pills or gelules containing 25 to 200 mg of active ingredient (1 to 5 per day), in the form of drops containing 0.25 to 5 % of active ingredient (10 to 40 drops -- 1 to 3 times per day), parenterally in the form of injectable ampoules containing 5 to 150 mg of active ingredient (1 to 3 per day) and rectally in the form of suppositories containing 10 to 100 mg of active ingredient (1 to 3 per day).

The gastric antisecretory, anti-ulcerous and spasmolytic properties of different compounds according to the invention were compared with a reference compound will-known in its use in gastroenterology, diphemanil (methylsulfate).

    __________________________________________________________________________     1°) Comparison of gastric antisecretory properties                                    Dose   Reduction of volume                                       Compound tested                                                                      DL 50 (mouse) (mg/kg/p.o.)                                                             administered (mg/kg/i.d.)                                                             of gastric secretion - (%)                                                                 ##STR34##                                     __________________________________________________________________________     73 0442                                                                               798    2.1    68         2.6                                            75 0009                                                                              1800    10     62         5.5                                            74 0180                                                                               716    1.5    86         2.1                                            73 0458                                                                              >200    2      19         <1                                             74 0145                                                                               180    1.6    88         9                                              75 0010                                                                              1200    25     82         21                                             74 0144                                                                               310    1.6    85         5.2                                            75 0012                                                                              1300    10     63         8                                              74 0159                                                                              1250    1.5    77         1.2                                            75 0102                                                                              1300    10     91         8                                              74 0186                                                                               360    1.5    67         4.2                                            74 0751                                                                              1100    4.5    69         4                                              74 0187                                                                              1600    1.5    78         0.9                                            74 0184                                                                              1300    1.5    77         1.2                                            74 0196                                                                              2100    1.5    74         0.7                                            74 0160                                                                              1700    1.5    45         0.9                                            Diphemanil                                                                            317    50     52         160                                            __________________________________________________________________________

This table shows that the compounds of the invention present gastric antisecretory properties generally superior to diphemanil (methylsulfate) at substantially lower doses.

    __________________________________________________________________________     2°) Comparison of anti-ulcerous properties                                            Dose   Percentage Reduction                                      Compound tested                                                                      DL 50 (mouse) (mg/kg/p.o.)                                                             administered (mg/kg/p.o.)                                                             of stress ulcers - (%)                                                                     ##STR35##                                     __________________________________________________________________________     73 0442                                                                               798    5.2    99         6.5                                            75 0009                                                                              1800    20     90         11                                             74 0180                                                                               716    7.7    100        11                                             75 0010                                                                              1200    20     77         17                                             73 0458                                                                              >2000   5      77         >2.5                                           74 0145                                                                               180    7.7    100        43                                             75 0011                                                                               120    20     51         170                                            74 0144                                                                               310    7.7    99         25                                             75 0012                                                                              1300    20     64         15                                             74 0159                                                                              1250    7.6    100        6                                              75 0102                                                                              1300    10     100        8                                              74 0186                                                                               360    7.4    98         21                                             74 0751                                                                              1100    11 (DE 50)                                                                            --         --                                             74 0187                                                                              1600    7.4    100        4.6                                            74 0184                                                                              1300    7.4    100        5.7                                            74 0196                                                                              2100    7.3    88         3.5                                            74 0160                                                                              1700    6      76         3.5                                            74 0195                                                                               2000   7.1    59         >3.5                                           Diphemanil                                                                            317    100    91         315                                            __________________________________________________________________________

This table shows that the compounds of formula (I) present anti-ulcerous properties very much superior the diphemanil since, administered at a dose such that the ratio ##EQU1## is at least equal to 170, they bring about a percentage reduction of stress ulcers between 51 and 100 %, whereas diphemanil administered at a dose such that the ratio ##EQU2## is equal to 315 brings about a percentage reduction of 91 %.

    __________________________________________________________________________     3°) Comparison of spasmolytic in vivo properties                                             Diminution of                                                           Dose   contractions of                                           Compound tested                                                                      DL 50 (mouse) (mg/kg/p.o.)                                                             administered (mg/kg/i.d.)                                                             the jejunum of a rabbit - (%)                                                              ##STR36##                                     __________________________________________________________________________     73 0442                                                                              798     26.5   67         33                                             74 0180                                                                              716     15.4   50         21                                             74 0144                                                                              310     15.5   43         50                                             74 0184                                                                              1300    14.9   39         11                                             74 0195                                                                              >2000   14.2   30         > 7                                            Diphemanil                                                                           317     20     70         63                                             __________________________________________________________________________

This comparison shows that the compounds according to the invention enable a spasmolytic effect in vivo to be obtained, at least equal to that resulting from the administration of diphemanil by administration of a dose representing a smaller fraction of the lethal dose.

This study then shows that the compounds of formula (I) provide an important technical progress as regards the prior art. 

What we claim is: pg,19
 1. A compound having the formula ##STR37## wherein Ar is α-furyl, α-thienyl, phenyl or phenyl substituted by one substituent selected from the group consisting of methoxy, alkyl having one to 4 carbon atoms, nitro and chloro, and the pharmacologically acceptable acid addition salts thereof.
 2. A compound as claimed in claim 1 in which Ar is phenyl.
 3. A pharmaceutical composition for use in the treatment of gastroduodenal ulcers, hypochlorohydrias, visceral spasms, asthma, hypertension, oedemas, and pains, comprising an effective amount of a compound as claimed in claim 1, in combination with a pharmaceutically acceptable carrier.
 4. A pharmaceutical composition according to claim 3 in the form of a tablet, pill or gelule containing 25 to 200 mg of said compound.
 5. A pharmaceutical composition as claimed in claim 3 in the form of an injectable composition in an ampoule wherein said ampoule contains 5 to 150 mg of said compound. 